This disclosure provides compositions that specifically bind to IL-21 and methods for the use of such compositions, e.g., for the treatment or prevention of an inflammatory or autoimmune disease or disorder.
IL-21 belongs to a family of cytokines that includes IL-2, IL-4, IL-7, IL-9 and IL-15, all of which bind to private (or shared) receptors in complex with the common cytokine receptor gamma-chain (γc). Most cytokines in this family are critically important for both the maintenance and function of T cells, B cells, and NK cells. The receptor for IL-21 is widely distributed on lympho-hematopoietic and non-hematopoietic cells, and IL-21 plays many roles.
For example, engagement of IL-21R by IL-21 leads to activation of several signaling pathways, including the Jak/STAT pathway (Davis, I D, et al., (2007) Clin Cancer Res 13, 3630-3636; Fuqua, C F, et al., (2008) Cytokine 44, 101-107; Habib, T, et al., (2002) Biochemistry 41, 8725-8731). More specifically, IL-21 activates STAT1, STAT3 and STATS, indicated by increased phosphorylation of these molecules within the cell (Asao, H, et al., (2001) J Immunol 167, 1-5; Diehl, S A, et al., (2008) J Immunol 180, 4805-4815; Scheeren, F A, et al., (2008) Blood 111, 4706-4715; Zeng, R, et al., (2007) Blood 109, 4135-4142). Activation of STAT3 in particular has been shown to play a critical role in regulating human B cell responses to IL-21 (Avery, D T, et al., (2008) J Immunol 181, 1767-1779; Avery, D T, et al., J Exp Med 207, 155-171).
Moreover, IL-21 contributes to maintenance and function of CD8+ memory T cells, and NK cells, promotes the generation of Th17 and T follicular helper (Tfh) cells in the mouse (and perhaps human), and inhibits regulatory T cells (Treg) cell generation. IL-21 has been shown to modulate the activity of NK cells including effects on their maturation growth and cytolytic activity (Spolski, R, and Leonard, W J, (2008) Curr Opin Immunol 20, 295-301). Additionally, IL-21 has been shown to promote IFNγ production by both primary NK cells as well as the human NK cell line, NK-92 (Kasaian, M T, et al., (2002) Immunity 16, 559-569; Strengell, M, et al., (2003) J Immunol 170, 5464-5469). IL-21 also has a variety of effects on non-hematopoietic cells, such as stromal cells where it induces inflammation through matrix metalloproteinase (MMP) release (Monteleone et al., (2006) Gut 55, 1774-1780).
One principal non-redundant role of IL-21 is the promotion of B cell activation, differentiation or death during humoral immune responses. The effect of IL-21 on human B cells has been extensively studied. IL-21 has a profound impact on B cell survival, activation, and proliferation as well as on the differentiation of B cells into Ig secreting plasma cells (PCs) (Avery, D T, et al., (2008) J Immunol 181, 1767-1779; Avery, D T, et al., J Exp Med 207, 155-171); Bryant, V L, et al., (2007) J Immunol 179, 8180-8190; Ettinger, R, et al., (2005) J Immunol 175, 7867-7879; Parrish-Novak, J, et al., (2000) Nature 408, 57-63; Pene, J, et al., (2004) J Immunol 172, 5154-5157). Furthermore, increased IL-21 production is characteristic of certain autoimmune diseases and is likely to contribute to autoantibody production as well as pathologic features of autoimmune disease. Activation of B cells in vivo can be driven by interactions with activated T cells that express costimulatory molecules such as CD40L and produce B cell tropic cytokines such as IL-21.
Overexpression of IL-21 is a feature of many inflammatory, immune-mediated, or autoimmune diseases or disorders, and is likely to be an important driver of autoantibody production as well as pathologic features of autoimmune disease (Nakou et al., (2013) Clin. Exp. Rheumatol. 31, 172-179). The critical role of IL-21 in promoting humoral immune responses makes it an important focus of potential therapeutic interventions in conditions characterized by over-production of both IL-21 and pathogenic autoantibodies (Dolff et al., (2011) Arthritis Res. Ther. 13, R157; Kang et al., (2011) Arthritis Res. Ther. 13, R179; McGuire et al., (2011) Immunity 34, 602-615; Liu et al., (2012) Arthritis Res. Ther. 14, R255; Terrier et al., (2012) Arthritis Rheum. 64, 2001-2011; Li Q et al., (2013) PLoS One 8, e68145; Li Y et al., (2014) Neurol. Sci. 35, 29-34). Neutralization of IL-21 in settings of autoimmunity is therefore expected to impact several cell populations believed to be involved in the pathogenesis of immune-mediated disease. Such diseases or disorders include, without limitation, vasculitis, e.g., Anti-neutrophil cytoplasm antibodies (ANCA) or giant cell arteritis (GCA) vasculitis, Sjögren's syndrome, inflammatory bowel disease, Pemphigus vulgaris, lupus nephritis, psoriasis, thyroiditis, Type I Diabetes, Idiopathic thrombocytopenic purpura (ITP), Ankylosing spondylitis, Multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease Myasthenia Gravis and Graft-versus-host disease (GVHD).
Anti-neutrophil cytoplasm antibodies (ANCA)-associated vasculitis (AAV) pathogenesis is typified by major autoantibodies to proteinase 3 (PR3) and myeloperoxidase (MPO). IL-21-producing CD4+ T cells are expanded in the blood (Abdulahad et al., (2013) Arth Res & Ther 15:R70). Elevated IL-21 is present in AAV serum relative to healthy controls, and exogenous IL-21 induces ANCA auto-antibody secretion in vitro from PBMCs isolated from AAV patients in vitro. AAV is made up of Granulomatosis with polyangiitis, formerly Wegener's granulomatosis, (GPA), eosinophilic granulomatosis with polyangiitis, also known as the Churg-Strauss syndrome (CSS) and microscopic polyangiitis (MPA). They are usually lumped together but epidemiologically the prevalence and distribution is different. Current treatments include corticosteroids, biological, e.g., rituximab, immunosuppressive drugs, antibiotics, or plasmapheresis, but the prognosis for patients remains poor. There remains an unmet need to find treatments for AAV.
Sjögren's syndrome (SS) is an autoimmune disease characterized by autoantibodies such as rheumatoid factor (RF) as well as autoantibodies to several nuclear antigens such as Ro/La. SS is the second most prevalent autoimmune condition after RA. There are at least 1 million primary Sjögren's patients in the US, of which 90% are female. SS affects salivary glands, causing, e.g., dry mouth and eyes. Additionally, SS may affect other organs of the body, including the kidneys, blood vessels, lungs, liver, pancreas, peripheral nervous system and brain and is associated with other autoimmune diseases such as lupus and rheumatoid arthritis. Highly elevated serum IL-21 levels correlate with increased IgG1 and the presence of autoantibodies (Kang, 2011). Elevated IL-21 and IL-21R levels can be found in ectopic follicles of salivary gland (Kang, 2011). Moreover, IL-21 is known to play a direct role in NK cell activation and cytotoxicity. Increased numbers of tissue-resident NK cells that overexpress the activating receptor NKp30 are found in salivary glands of primary Sjögren's syndrome patients, and correlate with focus score (Rusakiewicz et al., (2013) Sci. Transl. Med. 5, 195ra96). These NK cells are implicated in the pathogenesis of disease through direct NK cell-stromal cell cross talk resulting in tissue damage. IL-21 and its receptor are also expressed on salivary gland infiltrates (Kang, 2011), and IL-21 producing memory CCR9+CD4+ Tfh cells have been reported to be expanded in the circulation of most SS patients (McGuire, 2011). In addition, an increased level of Tfh cells in patients with elevated IL-21 is associated with extraglandular manifestations (Szabo et al., (2013) Clinical Immunol 147, 95-104). Preclinical animal models have demonstrated benefit from IL-21 inhibition (Liu et al. (2012) J Oral Pathol Med). There is no cure for SS; current treatments are of limited efficacy and none can be considered disease-modifying. Mild to moderate disease is treated symptomatically by over the counter medications. Severe disease is currently treated with hydroxychloroquine, steroids, methotrexate, azathioprine, or off-label rituximab. There remains an unmet need to find effective treatments for SS.
Neutralization of IL-21 has potential utility in several indications, including primary SS and vasculitis (Kang, 2011; Bae et al., (2012) Allergy Asthma Immunol Res. 4, 351-356; Terrier, 2012; Abdulahad, 2013; Szabo, 2013).
The effect of IL-21 on graft-vs-host disease (GVHD) has been extensively studied. When delivered by a hydrodynamic gene system, IL-21 has been shown to greatly accelerate human to mouse xenogeneic GVHD and found to increase B cells, plasma cells and immunoglobulin (Wu et al., (2013) Protein Cell 4, 863-871). Conversely, blockade of IL-21 in this system was reported to decrease gastrointestinal track injury, splenic Th1 cytokines, and protect from lethality (Hippen et al., (2012) Blood 119, 619-628). Moreover, protection from GVHD was reported to be dependent on the generation of Tregs (Hippen et al., 2012).
This disclosure provides compositions that specifically bind to IL-21, and methods for the use of such compositions, e.g., for the treatment or prevention of an inflammatory, immune-mediated, or autoimmune disease or disorder.
In a particular aspect, this disclosure provides for the treatment or prevention of GVHD using a composition comprising an antibody or fragment thereof that specifically binds to IL-21. For instance, it has been shown in a xenogeneic mouse model of GVHD that an anti-IL-21 composition blocks de novo-produced human IL-21. This composition potently inhibits GVHD-induced wasting disease and lethality when given both prophylactically, as well as therapeutically.